The Neurobiology of the Stress Resistant Brain

抗压大脑的神经生物学

• 批准号: 8098911
• 负责人: MONIKA FLESHNER
• 金额: $ 33.34万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098911
• 关键词: Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Autoreceptors; Behavior; Behavior Control; Behavioral; Brain; Clinical; Data; Development; Exercise; Genes; Goals; Housing; Human; Lead; Learned Helplessness; Medial; Mental Depression; Mental disorders; Neurobiology; Neurons; Perception; Physical activity; Prefrontal Cortex; Prevention; Proteins; Rat Strains; Rattus; Recruitment Activity; Resistance; Role; Running; Serotonin; Stress; System; Testing; Work; behavior test; biological adaptation to stress; density; desensitization; design; dorsal raphe nucleus; experience; fitness; improved; innovation; locus ceruleus structure; mRNA Expression; noradrenergic; novel strategies; prevent; protective effect; psychologic; public health relevance; relating to nervous system; resilience; stress related disorder; stress resilience; stressor

DESCRIPTION (provided by applicant): Identification of means to prevent stress-related psychiatric disorders such as depression & anxiety is of primary importance. One manipulation with established stress resilient effects is exercise. We have observed that rats allowed access to running wheels are protected against the depression- & anxiety-like consequences of uncontrollable stress, or learned helplessness (LH). Growing evidence indicates that LH behaviors are produced by hyperactivation & sensitization of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Hyperactivation of DRN 5-HT neurons during stress could lead to later sensitization of these neurons by desensitizing 5-HT1A inhibitory autoreceptors in the DRN. Results from our prior work & preliminary studies suggest that wheel running prevents LH by constraining the activity of DRN 5-HT neurons during stressor exposure & preventing the desensitization of 5-HT1A autoreceptors. Constraint over 5-HT neural activity could be an adaptive feature of the stress response that is dysregulated in stress-related psychiatric disorders but facilitated by prior voluntary exercise. Understanding how the experience of exercise is communicated to the DRN to result in stress resilience is a primary goal of this project that has clear clinical implications for the prevention of stress-related disorders. Exercise is a unique behavioral manipulation that will likely recruit neurocircuits that together result in unique adaptations in the brain. To facilitate identification of these neurocircuits, we propose an innovative approach of controllable / yoked uncontrollable wheel running. Although voluntary wheel running is associated with stress resilience, forced exercise often fails to produce stress protective effects despite considerable fitness benefits. These data suggest that activity or fitness per se is not sufficient to produce stress resilience. Instead, exercise plus the psychological variable of "perceived control" may be critical. This is an important distinction because it implies involvement of distinct neural substrates involved in the perception of control (such as the medial prefrontal cortex; mPFC), vs. those simply recruited by physical activity per se (such as the noradrenergic system), in the stress resilience produced by exercise. Indeed, we have observed that voluntary exercise recruits both of these systems; repeated activation of which could contribute to the increase in DRN 5- HT1A autoreceptors by inhibiting the activity of the 5-HT1A gene repressor Freud-1. The current project tests the hypotheses that 1) wheel running prevents LH by preventing DRN 5-HT1A autoreceptor desensitization &/or increasing mPFC-inhibition of the DRN during stress, 2) the effects of wheel running on behavior & 5-HT1A autoreceptors are dependent on exercise controllability, & 3) repeated activation of the mPFC &/or DRN 11- ADRs contribute to the increase in 5-HT1A autoreceptors & the protective effect of wheel running against LH. PUBLIC HEALTH RELEVANCE: The goal of the current proposal is to identify how the experience of exercise is communicated to the central serotonergic system to result in resilience against stress- induced anxiety, focusing specifically on central circuits converging on the 5-HT1A autoreceptor. The results of this work will improve our basic understanding of the effects of stressor exposure and exercise on serotonin systems, and could lead to novel approaches for the prevention or treatment of stress-related psychiatric disorders.

描述（由申请人提供）：识别预防与压力相关的精神疾病（例如抑郁症和焦虑）的方法至关重要。一种具有既定压力弹性效应的操纵是锻炼。我们已经观察到，可以保护大鼠进入跑步车轮，以防止无法控制的压力或学习的无助性（LH）的抑郁症和焦虑样后果。越来越多的证据表明，LH行为是通过在背部raphe核（DRN）中的5-羟色胺（5-HT）神经元的过度激活和敏化产生的。在压力期间，DRN 5-HT神经元的过度激活可能会导致这些神经元在DRN中的5-HT1A抑制性自身受体的脱敏，从而导致这些神经元的敏感性。我们先前的工作和初步研究的结果表明，在压力源暴露期间，旋转式运行可以通过约束5-HT神经元的活性来阻止LH，并防止5-HT1A自感受器的脱敏。对5-HT神经活动的约束可能是压力反应的适应性特征，在与压力有关的精神疾病中失调，但通过先前的自愿运动促进了压力反应。 了解如何将运动经验传达给DRN以导致压力韧性是该项目的主要目标，该目标对预防与压力相关的疾病具有明显的临床意义。锻炼是一种独特的行为操纵，可能会募集神经回路，从而导致大脑中独特的适应。为了促进这些神经电路的识别，我们提出了一种可控 /无法控制的车轮运行的创新方法。尽管自愿的车轮跑步与压力弹性有关，但尽管有很大的健身益处，但强迫运动通常无法产生压力保护作用。这些数据表明活动或健身本身不足以产生压力弹性。相反，运动加上“感知控制”的心理变量可能至关重要。这是一个重要的区别，因为它意味着参与对照感知的不同神经底物（例如内侧前额叶皮层； MPFC），而与简单的体育活动本身募集的那些（例如甲肾上腺素能系统），在锻炼中产生的压力恢复力。确实，我们观察到自愿运动招募了这两个系统。反复激活可能会通过抑制5-HT1A基因抑制剂Freud-1的活性来导致DRN 5-HT1A自身受体的增加。当前的项目测试1）通过防止DRN 5-HT1A自身感受器脱敏和/或增加压力下DRN的MPFC抑制作用来阻止LH的假设，2）行为对行为＆5-HT1A自身访问的影响依赖于运动可控性，＆3）重复促进了MPFC＆/或DREN的激活，＆3） 5-HT1A自身受体和旋转对抗LH的保护效果。 公共卫生相关性：当前建议的目的是确定如何将运动经验传达给中央血清素能系统，从而导致抵御压力引起的焦虑的韧性，专门集中于在5-HT1A自身受体上汇聚的中央电路。这项工作的结果将改善我们对压力源暴露和运动对5-羟色胺系统的影响的基本理解，并可能导致预防或治疗与压力相关的精神疾病的新方法。